| DISCOVERY |
A New Way To Fight Bacteria Inhibitor blocks biosynthesis of key bacterial iron-scavenging agent STU BORMAN COLLABORATIVE GROUP Tan (from left), Jae-Sang Ryu, Julian A. Ferreras, and Quadri identified and tested a novel inhibitor of siderophore biosynthesis. Coworker Federico Di Lello is not shown. PHOTO BY CHERYL VOS A novel strategy for fighting bacterial infections has been demonstrated: blocking bacterial biosynthesis of siderophores, compounds that make it possible for certain bacteria to obtain iron, which they require to grow and to cause disease. An inhibitor of the initial step in siderophore biosynthesis was designed by Derek S. Tan of Memorial Sloan-Kettering Cancer Center, New York City; Luis E. N. Quadri of Weill Medical College of Cornell University, also in New York City; and their coworkers. The inhibitor blocks siderophore production in Mycobacterium tuberculosis, the cause of tuberculosis (TB), and Yersinia pestis, the cause of bubonic and pneumonic plague and one of the most virulent bacteria known (Nat. Chem. Biol. 2005, 1, 29). The agent--5'-O-(N-salicylsulfamoyl)adenosine (salicyl-AMS)--is the first potent and biochemically verified inhibitor of siderophore biosynthesis. It could serve as a lead compound for discovery of anti-TB and antiplague drugs. Agents that inhibit the production of siderophores may have fewer side effects than conventional antibiotics, because siderophore biosynthesis occurs only in bacteria and not in humans. The strategy can also potentially be extended to other diseases caused by bacteria that rely on siderophores. Iron is an essential trace nutrient for most bacteria. In humans and other mammalian hosts of bacteria, Fe3+ ions are usually bound to proteins such as the transferrins. Bacteria produce and secrete siderophores to extract iron from the host's proteins and transport it back to bacterial cells. Tan, Quadri, and coworkers proposed that a compound that mimics an intermediate in the initial step of bacterial siderophore biosynthesis might block siderophore production. Guided by a structural analysis of enzymes that catalyze that step, they synthesized salicyl-AMS and found that it inhibits siderophore production and growth (under Fe3+-limited conditions) in the bacteria that cause TB and plague. Mohamed A. Marahiel of Philipps University of Marburg, in Germany, calls the strategy "a nice and general approach" but notes that although salicyl-AMS is a potent inhibitor, there is still a need for "an optimized inhibitor with better membrane-penetrating properties to enhance in vivo uptake." Samuel J. Danishefsky, a colleague of Tan's at Memorial Sloan-Kettering, says the approach has "major potential applications in global public health and biodefense. It is also an excellent demonstration of the power of collaborative multidisciplinary research, combining Tan's striking abilities as a synthetic chemist with Quadri's as a biochemist and microbiologist." |
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